Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the gastrointestinal tract with no available permanent cure. Conventional IBD treatment relies on systemically acting anti-inflammatory and immunosuppressive agents. The current treatments face a range of problems related to their cost, systemic immune suppression and increased cancer risk. There is a great need and potential for novel treatments, especially if those treatments can be delivered locally to the site of intestinal inflammation by oral route. One of the hallmarks of IBD is the activation of immune cells and the production of proinflammatory cytokines such as TNF?. Furthermore, the chemokine receptor CXCR4 is ubiquitously overexpressed in inflamed intestinal mucosa. Both TNF? and CXCR4 levels are increased in IBD and represent an exciting putative combination target for local combination therapy. The objective of this proposal is to develop and test novel dual-function particles for combination oral treatment designed to safely reduce colonic inflammation. The central hypothesis is that the proposed combined approach will result in improved treatment of IBD as a result of decreased inflammation due to anti-TNF? siRNA and inhibition of CXCR4 by polymeric CXCR4 antagonists (PCXA). The hypothesis is based on (i) available evidence that blockade of TNF? reduces local inflammation in IBD and (ii) our current studies, which demonstrate that PCXA alone enhances healing of experimental IBD in mice. The overall objective of this application will be achieved by pursuing two specific aims: 1) design PCXA capable of oral delivery of siRNA; and 2) evaluate effectiveness of the combined TNF? silencing and CXCR4 antagonism of PCXA/siRNA in a mouse model of IBD. Design of delivery vectors that exhibit their own pharmacologic activity independent of the delivered therapeutic agent represents innovative approach to combination therapies of IBD. The proposed research is significant because it will establish a novel platform for simultaneous targeted local delivery f CXCR4 antagonists and anti-inflammatory siRNA to improve delivery for better treatment and outcome of IBD.